Chronic obstructive bronchitis and emphysema chronic obstructive airway disease (COAD, COLD) ( chronic obstructive pulmonary disease ) COPD

COPD emphysema bronchitis „pink puffer” „blue bloater”

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 Proportion of 1965 Rate 3.0 Coronary Heart Disease Stroke Other CVD COPD All Other Causes 2.5 2.0 1.5 1.0 0.5 –59% –64% –35% +163% –7% 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998

Evidence-based medicine (The Global Burden of Disease study) (Science 1996; 274:740-743.)

Epidemiology 4-7% of adult population ( 600 million patients worldwide) Prevalence expected to rise 3x in 10 years. By 2020, it becomes the 3rd most frequent cause of death ( 4,7 million cases of death – WHO, 1999)

COPD morbidity in Hungary

Definition COPD is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarly caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences. ATS/ERS Task Force, 2004

CIBA Guest Symposium: Terminology, definitions and classifications of chronic pulmonary emphysema and related conditions (1959) 1./ Obstructive emphysema: abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of the alveolar walls and without obvious fibrosis. 2./ Chronic bronchitis: the presence of chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes (heart failure, tbc, bronchiectasis, tumor, lung abscess) of chronic cough have been excluded. 1

Differential diagnosis of airway obstruction Chronic bronchitis Emphysema COPD Airflow obstruction Adapted from Snider GL. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med. 1995; 152: S77–S121 Asthma Adapted from Snider 1995

Etiology: host factors

Etiology: acquired risk

Effect of smoking on annual decline in lung function Fletcher C, Peto R: BMJ 1977:i: 1645

T lymphocytes in COPD * p<0.05 with healthy nonsmokers § p<0.05 with stable CB Zhu J et al. AJRCCM 2001; 164: 109-16 15

Cells orchestrating the inflammation in COPD

Oxidativ stress epithel, macroph.

Pathology Large airways: goblet cell metaplasia, increased mucus production Medium and small airways ( 7-9. generation): inflammation similar to asthma in certain patients Small airways ( 13 - 15. generation) : bronchial wall inflammation, degeneration, fibrosis Alveoli: elastin loss and alveolar surface loss

Loss of alveolar attachments in smokers Saetta M, Ghezzo H, Kim WDM, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis 1985; 132: 894-900 Normal Smoker Saetta et al. ARRD 1985

Airway muscle thickness Increase in COPD Non-smoker COPD © M Saetta Saetta. 1998

Small airways in COPD Barnes, NEJM,2004

Causes of Airflow Limitation Irreversible Fibrosis and narrowing of the airways Loss of elastic recoil due to alveolar destruction Destruction of alveolar support that maintains patency of small airways

Causes of Airflow Limitation Reversible Accumulation of inflammatory cells, mucus, and plasma exudate in bronchi Smooth muscle contraction in peripheral and central airways Dynamic hyperinflation during exercise

Airflow limitation Driving pressure (parenchyma) = Resistance (small airways)

Structure - function relationships in COPD EMPHYSEMA SMALL AIRWAYS ABNORMALITIES Alveolar wall destruction Air space enlargement Capillary network reduction Alveolar attachments loss Small airways narrowing Airway wall thickening Adapted from Barberà JA, Ramírez J, Roca J, et al. Lung structure and gas exchange in mild chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141: 895-901 . . . . High VA/Q areas Low VA/Q areas Barberà et al. ARRD 1990

COPD asthma neutrophils no AHR* no bronchodilation no corticosteroid effect eosinophils AHR* good bronchodilator effect good corticosteroid effect 10 – 40 % “ Wheezy bronchitis ” reversibility threshold: 12 –15% (>200ml) FEV1- increase *AHR= airway hyperreactivity

Characteristics of phenotypes bronchitis emphysema Dynamic lung volumes decreased decreased ( FEV1 , FEV1/FVC) Static lung volumes TLC normal or mild increase increased RV moderate increase increasd Diffusion capacity normal or mild decreased decrease Blood gas hypoxaemia, hypercapnia hypoxaemia in end-stage exercise hypoxaemia: no change, improves hypoxaemia or deteriorates deteriorates Cor pulmonale frequently seldom

Classification ( GOLD 2006 ) FEV1 (ref%* ) symptoms cough, sputum mild  80 % morning sputum, ( FEV1/FVC  70% ) minimal breathing dyscomfort moderate 50 - 80 % dyspnea on moderate exertion with or without wheezing, discolored sputum, severe 30 – 50 % acute worsening with infection, with significant erosion of QoL very severe < 30% n cough, wheezing, breathlessness on minimal exertion signs of RHF, significantly impaired QoL

Pharm.spir. Beta-2 agonist Parasympatho- lytics Xantin derivate

Systemic consequences/comorbidities in COPD Expiratory flow limitation Air trapping Exacerbation Hyperinflation Dyspnea Reduced exercise tolerance Életminőség Inactivity In patients with COPD, there is a cycle of airflow limitation, dyspnea, and reduced exercise endurance. The physiological impairment in COPD is characterized by airflow limitation, air trapping, and hyperinflation. These physiologic abnormalities lead to dyspnea (or breathlessness). Dyspnea in itself is unpleasant, and it also severely limits the amount of activity a patient can undertake. Often patients will avoid situations that demand physical activity. Avoiding exercise leads to deconditioning and worsening of the disease and, ultimately, the patient’s health-related quality of life suffers. COPD is often associated with acute exacerbations of symptoms. Exacerbations are periodic worsenings of disease that are often triggered by respiratory tract infections. As COPD worsens, patients are more likely to experience exacerbations, which become more severe. Exacerbations may have a long-term impact on the disease and can contribute to premature mortality. Deconditioning Systemic consequences e.g. Muscle atrophy/wasting, CHD depression, osteoporosis, anaemia

Airway inflammation and systemic consequences in COPD (theory) Tüdő Inzulin resistance, II. type diabetes Muscle wasting/atrophy TNFa IL-6 ? Local inflammation Osteoporosis Cardiovascular events CRP Liver

GOLD Workshop Report Four components of COPD Management Asses and monitor disease Reduce risk factors Manage stabil COPD Education PharmacologicGyógyszeres Non-pharmacologic Manage exacerbations

Treatment of COPD (GOLD 2003) inhalative corticosteroids Surgical treatment ? longterm oxigen treatment (chronic respiratoryy failure) inhalative corticosteroids (  3 exacerbation in the previous 3 years) One or more long acting bronchodilators, rehabilitation Short acting anticholinergic and/or 2-agonist as needed Avoidance of risk factors, influenza vaccination FEV1  80% 50%  FEV1 < 80% 30%  FEV1 < 50% FEV1 < 30% or without or with symptoms chronic respiratory or right heart failure airway obstruction (FEV1/FVC < 70%) I. mild II. moderate III. severe IV. very severe

Respiratory insufficiency in COPD acute exacerbation pink puffer blue bloater partial global (hypoxaemic/transfer failure) (pump-, ventilatory failure)

Non-invasive mechanical ventilation in respiratory insufficiency

wheezing, chest tightness, increased cough and sputum purulence Main symptomps in acute exacerbation of COPD increased dyspnea wheezing, chest tightness, increased cough and sputum purulence +/- reduced exercise tolerance, fever , change in chest x-ray, leukocytosis malice, disturbed sleep, daytime sleepiness, depression, confusion (CO2 retention)

AE COPD  hospitalisation  re-admission  death Several studies have analysed the impact of COPD exacerbations leading to hospitalisation. Being hospitalised for a COPD exacerbation has been shown to be a key risk factor for re-hospitalisation and premature death, with mortality rates between 23% and 43% within one year after the event. 1Eriksen, Ugeskr Laeger 2003 2Groenewegen, Chest 2003 3Almagro, Chest 2002 4Connors, Am J Respir Crit Care Med 1996

Exacerbations of COPD Viral infections (Rhino,Infl, Parainfl,Adeno, RSV) Bacterial infections (H.i.,S.p.,M.c.,P.a.,S.a., Enterobact.), atypical( M.p., C.p.) Inhalation of environmental irritants (NO2, SO2, PM10, ozone) deviation from diet Predisposing factors (smoking, severe comorbidity, bacterial colonisation in the stable phase) 42

New strains of bacteria and AE COPD Sethi, NEJM 2002 Timeline and molecular typing for a patient with chronic obstructive pulmonary disease. The horizontal line is a timeline, with each number indicating a clinic visit. The arrows indicate exacerbations. Isolates of Haemophilus influenzae were assigned types based on banding patterns on gel electrophoresis. The gel on the right shows whole bacterial cell lysates of isolates recovered at visits 5 through 9. A, B, and C indicate the molecular types based on banding patterns. Molecular mass standards are noted on the left of the gel in kilodaltons. H.influenzae with new antigen structure Immune and inflammatory response AE

Role of antibiotics - „fall and rise „ hypothesis Miravitlles M, ERJ 2002 The "fall and rise" hypothesis of bacterial exacerbations of COPD. Some patients with COPD show bacterial colonisation of the lower airways. This colonisation is usually due to potentially pathogenic microorganisms (PPMs) in low concentrations. Under specific circumstances, these PPMs may proliferate and produce an increased inflammatory reaction in the host. When this proliferation exceeds a certain clinical threshold (– - –), symptoms of acute exacerbation (AE)appear. Under antibiotic (AB) therapy (–––: AB1; - - - -: AB2; – – –: AB3), the concentration of PPMs decreases, and, when the threshold is crossed again, the clinical symptoms disappear (cure (C)). When the intensity and speed of the bactericidal activity of the AB is increased, recovery occurs more rapidly and the time to the next exacerbation (double-headed horizontal arrow) is prolonged. AB activity produces a "fall" in bacterial concentrations, which, if not completely eradicated after the pressure of the antimicrobial agent is removed, "rise" again. Some modifying factors may change the threshold of clinical symptoms (double-headed vertical arrow).

Are antibiotics needed? (Procalcitonin Guided Therapy) Standard group Procalcitonin group Christ Crain, Lancet 2004 P=0.03 P<0.0001 P=0.003 P=0.003 P<0.0001 45/45 9/9 100 38/42 27/31 80 2/3 60 16/31 Antibiotic prescriptions (%) 40 11/29 PCT (ng/ml) < 0,1 bacterial infection very unlikely no antibiotics recommended, 0,1 – 0,25 bacterial infektion unlikely antibiotics only, if infection seems clinially probable 0,25 – 0,5 bacterial infektion probable antibiotcs recommended > 0,5 bacterial infektion probable, antibiotcs strongly recommended 20 4/28 2/15 0/10 CAP AECOPD Bronchitis Asthma Others PCT (ng/ml) - < 0,1 not recommanded - > 0,5 strongly recommanded

Antibacterial treatment of AECOPD pathogens treatment 1./ acute tracheobronchitis atipical agent ? macrolide ? 2./ Chronic bronchitis H. influenzae aminopenicillin/cv without comorbidity M. catarrhalis cefalo. II, III ( FEV1 > 50% ) res. S. pneumoniae ? makrolide II. 3./ Chronic bronchitis with „ „ comorbidity ( FEV1 < 50% ) res. Pneumococcus ! respiratory kinolon 4./ Chronic bronchial infection „ respiratory kinolon Gram-neg enterobact. Ps. eruginosa = ciprofloxacin 11

COPD Exacerbation - Steroids COPD, no steroids 30 pack-years FEV1 < 1,5 l Group A: Placebo Group B: Methylprednisolone 4x125 mg i.v. tappering until day 14 Niewoehner DE. N Engl J Med 1999; 340: 1941-47 50

Antibiotic Consumption in 26 Countries Goossens.HA. Lancet 2005; 365:579-87 51

Penicillin resistent S.pneumoniae EARSS, 2006